CH634074A5 - METHOD FOR PRODUCING NEW CEPHEMCARBONIC ACID DERIVATIVES. - Google Patents

Description

The object of the invention is therefore to provide new 7-position sub-30 substituted 2-lower alkyl-2- or -3-cephem-4-carboxylic acid derivatives and their pharmaceutically acceptable salts which are effective against a number of pathogenic microorganisms are active.

DE-OS No. 2 412 513 describes a general acylie-35 ranking process for cephemcarboxylic acid derivatives, but the present process is neither disclosed nor described in examples.

The new compounds obtainable according to the invention correspond to the general formula:

40

R-

N

ts

A-CONH

45

R-

N "

tr

A-CONH

where R1 is lower alkyl,

50 R2 for a carboxy or an esterified carboxy group

0 1 stands,

C 0 OH r3 represents an amino or an acylamino group and

A for carbonyl, hydroxy (lower) alkylene, hydroxyimino or a salt thereof is subjected to an esterification reaction. (low) alkylene or lower alkoxyimino (low) alkylene,

8. The method according spoke 1, characterized in that the last two groups with respect to the group that in the formula IA for carbonyl or hydroxy (low) alky- _CQNH- have the syn or the anti configuration,

len stands,

9. The method according spoke 8, characterized in that R1 is lower alkyl, preferably methyl, R2 is carboxy, lower alkoxycarbonyl, which may have 1 to 3 halogen atoms, or lower alkanoyloxy (lower) alkoxycarbonyl, preferably carboxy, R3 is amino or Lower alkanoylamino, which may have 1 to 3 halogen atoms, preferably amino or formylamino, and A is carbonyl or hydroxy (lower) alkylene, preferably hydroxymethylene.

10. The method according to claim 1, characterized in that R1 stands for lower alkyl, R2 for carboxy or a different

The process according to the invention is characterized in that a compound of the general formula:

60H2N

65

(II)

or their reactive derivative on the amino group or their salt with a compound of the formula:

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N "

R-

t

A-COOH

S "

R3a — n - * -

CONH

0

or their reactive derivative on the carboxy group or their salt.

(III) The compounds prepared according to the invention can be subjected to the following reactions:

S- _pl p

rì

■ Kv "

(Ib)

RF or a salt thereof

N-

t

VS '

N — n H2N ff- yy— A-

CONH

y

-N

or a salt of it

S- -R1

2 (Ia)

Elimination of the amino protecting group

This method is defined in claims 2, 3 and 4.

N "

R3 ft

(Ii)

or a salt of it

A-CONH

0

N "

r — rr

A-CONH

0

(Ih)

or a salt of it.

This method is defined in claims 5 and 6.

■ N

-R

R

2a ri

NV,

00H

<-

Elimination of the carboxy protecting group

3 N R ft

:>

A-CONH

0

(Ih)

or a salt of it

N-

R ff - A-CONH

(Ij)

or a salt of it.

rsi

■ Rsv

C00H

-R

C00R-

<-

Esterification

5

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This method is defined in claim 7. In the methods according to DE-OS 2 412 513 are prepared, the above formulas R2a represent an esterified carboxy group, among the starting compounds of formula III can

R3a for an acylamino group and R5 for an ester portion of a new compound esterified carboxy group of formula -COOR5 prepared by conventional methods. which are represented by the following process schemes

The starting compounds of formula II can according to the 5 can.

H2N.

N '

(VII)

Acylation -z a N ~

ck2-z R - ~ tr

S

(Illa)

Oxida-c "-z tlo">

or its reactive derivative on the amino group or a salt thereof

(HId)

(IIIf)

> R

where Z is a protected carboxy group.

With regard to the compounds (I) and (Ia) to (Ij) and the “starting compounds (III), (Illa) to (Illh) and (VII), it is pointed out that these can take tautomeric forms. If a group of the formula:

R

N —- ast

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is contained in the molecules of the compounds obtainable according to the invention and the starting compounds, then this group can alternatively by its tautomeric formula:

H N-i wherein R3 'represents an imino or acylimino group. That is, both groups are in a state of equilibrium with one another. This tautomerism can be represented by the following equation:

r:

>

<-

R

HN-—

Ji

3 'S

These types of tautomerism between the amino compound and the corresponding imino compound, as indicated above, are well known in the literature. It will be apparent to those skilled in the art that the tautomeric isomers are readily mutable and that they should be included in the same category of compound per se.

Accordingly, both tautomeric forms of the compounds (I) and (Ia) to (Ij) and the starting compounds (III), (Illa) to (Illh) and (VII) obtainable according to the invention clearly fall within the scope of the present invention. Herein, the compounds obtainable according to the invention and the starting compounds which contain the group of such tautomeric isomers are always described only in one form for this, i.e. of the formula:

a

R S

specified, but what happens for the sake of simplicity.

With regard to the compounds (I), (Ia) to (Ib) and (Ih) to (Ij) obtainable according to the invention and the starting compounds (III), (Ille) to (Illh) and (VIII), it is further pointed out that the compounds according to the invention available compounds and the starting compounds include synisomers, antiisomers and mixtures thereof. If a hydroxyimino or lower alkoxyimino group is present in the molecules of the starting compounds obtainable according to the invention, the compounds obtainable according to the invention and the starting compounds are present as synisomers or antiisomers or as mixtures thereof. Herein, a synisomer means a geometric isomer, which is a partial structure of the following formula:

-C-Z

-C-COOH

-C-CONH-

N-OR4 or N-OR4 or N-OR4

Has. The anti isomer is the other geometric isomer, which is a partial structure of the following formula:

-C-Z -C-COOH -C-CONH-

II II II

R40-N or R40-N or R40-N

in which R4 and Z each have the meanings given above.

Suitable pharmaceutically acceptable salts of the compounds (I) obtainable according to the invention are conventional non-toxic salts. Examples of these are metal salts, such as alkali metal salts (for example the sodium salt, potassium salt etc.) and earth-5 alkali metal salts (for example the calcium salt, magnesium salt etc.), the ammonium salts, the salts with organic bases (for example the trimethylamine salt, triethylamine salt, pyridine salt, picolin salt, Dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt etc.), salts with organic acids (e.g. the acetate, maleate, tartrate, lo-methanesulfonate, benzenesulfonate, toluenesulfonate etc.) and salts with inorganic acids (e.g. the hydrochloride, hydrobromide, sulfate, phosphate etc.) or salts with an amino acid (e.g. with arginine, aspartic acid, glutamic acid and the like) and the like.

15 The term “low” as used herein is intended to mean groups of 1 to 6 carbon atoms unless otherwise stated.

Suitable lower alkyl groups are e.g. Methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like. Suitable examples of the ester portion in the esterified carboxy group are e.g. the lower alkyl ester (such as the methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, pentyl ester, hexyl ester, 1-cyclopropyl ethyl ester etc.), which may have at least one suitable substituent, such as 25 e.g. Lower alkyl alkoxy (lower) alkyl esters (such as acetoxy methyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 2-acetoxy ethyl ester, 2-propionyloxy ethyl ester etc.), lower alkanesulfyl ester, etc. and mono 30 (or di- or tri) halogen (lower) alkyl esters (e.g. the 2-iodoethyl ester, 2,2,2-trichloroethyl ester etc.), lower alkenyl esters (e.g. the vinyl ester, allyl ester etc.), lower alkynyl esters (e.g. the ethyl ester, propinyl ester, etc.), ar (lower) alkyl esters which may have at least one suitable substituent (for example 35 of the benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenyl methyl ester, bis (meth-oxyphenyl) methyl ester , 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.), Ajyl esters, which may have at least one suitable substituent (e.g. the phenyl-40 ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, Xy lylester, Mesitylester, Cumenylester etc.) and the like.

Suitable acyl groups in the acylamino group R3 are e.g. Carbamoyl. aliphatic acyl groups and acyl groups containing an aromatic or heterocyclic ring. 45 Examples of such acyl groups are e.g. Lower alkanoyl

(e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, .isovaleryl, oxalyl, succinyl, pivaloyl etc.), lower alkoxycarb-onyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarb-onyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, 50 butoxycarbonyl, 50. -Butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl etc.), lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.), arylsulfonyl (e.g. benzenesulfonyl, tosyl, etc.), aroyl (e.g. benzoyl, toloyl, phyloyl, phyloyl, Indancarbonyl 55 etc.), Ar (low) alkanoyl (e.g. phenylacetyl, phenylpropionyl etc.), Ar (low) alkoxycarbonyl (e.g. benzyloxycarbonyl etc.) and the like.

The above acyl moiety may contain at least one suitable substituent, e.g. Halogen (e.g. chlorine, 60 bromine, iodine or fluorine), cyano, lower alkyl (e.g. methyl,

Ethyl, propyl, isopropyl, butyl, etc.), lower alkenyl (e.g., vinyl, allyl, etc.) or the like.

Individual examples of this are mono-, di- or tri-halogen (low) alkanoyl, e.g. Trifluoroacetyl etc.

Suitable lower alkylene parts in the designations hydroxy (lower) alkylene, hydroxyimino (lower) alkylene and lower rigoxyoxyimino (lower) alkylene are e.g. Methylene, ethylene, trimethylene, propylene, tetramethylene and the like.

65

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Suitable lower alkoxy parts in the designation lower alkoxyimino (lower) alkylene are e.g. Methoxy, ethoxy, prop-oxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.

Suitable ester parts of esterified carboxy groups are e.g. the esters exemplified for the protected carboxy group.

Suitable residues of an acid are e.g. Halogen (e.g. chlorine, bromine, iodine or fluorine) and the like.

The method according to the invention is explained in more detail below:

The new compounds (I) and the salts thereof are prepared by treating the compound (II) or its reactive derivative on the amino group or a salt thereof with the compound (III) or its reactive derivative on the carboxy group or a salt implement it.

Suitable reactive derivatives on the amino group of compound (II) are e.g. the Schiff base type imino isomer or its enamine type tautomeric isomer formed by reacting Compound (II) with a carbonyl compound such as acetoacetic acid or the like; the silyl derivative obtained by reacting Compound (II) with a Silyl compound such as bis (trimethylsilyl) acetamide or the like is formed, and the derivative formed by reacting the compound (II) with phosphorus trichloride or phosgene and the like.

Suitable salts of the compounds (II) and (III) are e.g. Acid addition salts, for example salts with organic acids (e.g. the acetate, maleate, tartrate, benzenesulfonate, toluene sulfonate etc.) or salts with inorganic acids (e.g. the hydrochloride, hydrobromide, sulfate, phosphate etc.), metal salts (e.g. the sodium salt, Potassium salt, calcium salt, magnesium salt etc.), the ammonium salt, organic amine salts (e.g. the triethylamine salt, dicyclohexylamine salt etc.) and the like.

Suitable reactive derivatives on the carboxy group of compound (III) are e.g. the acid halide, the acid anhydride, the activated amide, the activated ester and the like. Examples of these are an acid chloride, e.g. an acid azide, a mixed acid anhydride with an acid, such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid etc.), dialkylphosphoric acid, sulfuric acid, thiosulfuric acid, carbonic acid, carbonic acid, sulfuric acid e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloresacetic acid etc.) or aromatic carboxylic acids (e.g. benzoic acid etc.), symmetric acid anhydrides, amides which have been activated with imide-azole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole and activated esters (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl

[(CH3) 2N = CH -] - ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, penta-chlorophenyl ester, mesyl-phenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-carboxymethylthioester , Pyranyl esters, pyridyl esters, piperidyl esters, 8-quinolyl thioesters etc.) or esters with an N'-hydroxy compound (e.g. N, N-dimethylhydroxylamine, l-hydroxy-2- (lH) -pyridone, N-hydroxysuccinimide, N- Hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole etc.) and the like. These reactive derivatives can be selected as desired depending on the type of compound (III) used.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction . These conventional ones

Solvents can also be used in a mixture with water.

If the compound (III) is used in the free acid form or in salt form in the reaction, the reaction 5 is preferably carried out in the presence of a conventional condensing agent, e.g. of N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N'cyclohexyl-N '- (4-diethylaminocyclohexyl) carbodiimide, N, N'-di-ethylcarbodiimide, N, N'- Diisopropylcarbodiimide, N-ethyl'N '- (3-io dimethylaminopropyl) carbodiimide, N, N-carbonylbis- (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1- Alkoxy-l-chloro-ethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl poly-phosphate, phosphorus oxychloride, phosphorus trichloride, thionyl-15 chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxy-benzisoxazolium salt, 2-ethyl-5-m (5-) -isoxazolium-hydroxide-intramolecular salt (chloromethylene) -dimethylammonium chloride, l- (p-chlorobenzoisulfonyloxy) -6-chloro-lH-benzotriazole or the like.

-o The reaction can also be carried out in the presence of an inorganic or organic base, e.g. of alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorphorin, N, N-di (lower) alkylbenzylamine or the like. The reaction temperature is not critical and the reaction can usually be carried out under cooling or at ambient temperature.

It should be noted that in order to prepare a synisomer of the new compounds (I) selectively and with high yield, it is expedient to select suitable conditions. For example, a synisomer of the desired compounds (I) can be obtained selectively and in high yield by carrying out the reaction of the compound (II) with the corresponding synisomer of the starting compound (III) in the presence of a Vilsmeier reagent, for example such a as it is made from dimethylformamide and phosphorus oxychloride or the like. In particular, a synisomer of the new compounds (I) in which R3 is amino can be obtained well if the reaction is carried out in the presence of more than two molar equivalents of phosphorus-40 oxychloride against any amount of the corresponding synisomer of the starting compound (III), where R3 is amino and dimethylformamide. Particularly good results can be obtained if an activation step of the synisomer of the starting compound (III), in which R3 is 45 amino, is carried out in the presence of a silyl compound, e.g. of bis (trimethylsilyl) acetamide, trimethylsilylacetamide or the like.

The new compounds (Ia) or the salts thereof can be prepared by subjecting an obtained compound (Ib) 50 or a salt thereof to an elimination reaction of the acyl group.

Suitable salts of compound (Ib) are e.g. Metal salts, ammonium salts and organic amine salts, as exemplified for the compound (II). 55 Elimination can take place in particular by hydrolysis or reduction. The hydrolysis can also be carried out using an acid or base or hydrazine and the like. These methods can be selected depending on the type of acyl group to be eliminated.

Among these methods, acid hydrolysis is the most common and preferred method of elimination e.g. of substituted or unsubstituted alkoxycarbonyl, cy-cloalkoxycarbonyl, substituted or unsubstituted aralk-oxycarbonyl. Suitable acids are e.g. organic or inorganic 63 acids, such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid and the like. Best suited is an acid that is easily removed from the reaction mixture by conventional means, for example

634 074 8

can be removed by distillation under reduced pressure, such as acid (e.g. acetic acid, propionic acid, hydrochloric acid etc.). Formic acid, trifluoroacetic acid etc. The acids can be like the reduction in the presence of a metal catalyst. Me, depending on the type of protective group to be eliminated, metallic catalysts for catalytic reduction are e.g. Platinum can be selected. If the elimination reaction is carried out with a catalyst (for example platinum wire, spongy platinum, pia acid, then it can be carried out in the presence or in 5 tin black, platinum colloid etc.), palladium catalysts (for example in the absence of a solvent. Suitable spongy palladium, palladium black, Palladium-nete solvents are, for example, water, conventional organic oxide, palladium on barium sulfate, palladium on barium carbosolvent or mixtures thereof The hydrolysis with hydranate, palladium on charcoal, palladium on silica gel, palladium is usually used to protect amino groups - Dium colloid etc.), nickel catalysts (e.g. reduced nickel, phthaloyl-type pen. io nickel oxide, Raney nickel, Urushibara nickel etc.) and the like

Reductive elimination is generally used.

det, e.g. Haloalkoxycarbonyl (e.g. trichloroethoxycarbo-

nyl etc.), substituted or unsubstituted aralkoxycarbonyl The reaction temperature is not critical. It can

(e.g. benzyloxycarbonyl etc.), 2-pyridylmethoxycarbonyl, etc. according to the nature of the protective group of the carboxy group and to be removed. Suitable reduction processes are e.g. the re-15 of the elimination method can be selected.

production with an alkali metal borohydride (e.g. sodium borohydrate). The new compounds (Ij) or salts thereof can be

drid, etc.), the reduction can be made with a combination of one by making a compound obtained (Ih)

Metal (e.g. tin, zinc, iron, etc.) or the metal and one or a salt thereof is subjected to an esterification reaction. Metal salt compound (e.g. chromium (II) chloride, chromium (II) ace- Suitable salts of the compound (Ih) are, for example, such as tat, etc.) and an organic or inorganic acid (for example 20 sje in connection with the compound ( II) Acetic acid, propionic acid, hydrochloric acid etc.) and the catalytic esterification agent used in the reaction can

Reduction. Suitable catalysts are e.g. the conventional compound of the general formula:

Chen catalysts, such as Raney nickel, platinum oxide, palladium

on charcoal and the like. X-R5 (XI)

The acyl group can generally be eliminated by hydrolysis. In particular, the trifluoroacetyl group in which R5 has the above meaning and X for hydroxy or one can be easily eliminated by standing approximately at a neutral-bed reactive derivative thereof.

treated with water. Halogen substituted alkoxycar- Suitable examples of reactive derivatives of hydroxy-bonyl and 8-quinolyloxycarbonyl groups will usually be e.g. Residues of acids as mentioned above by treatment with a heavy metal such as copper, zinc 30.

or the like is eliminated. The reaction is usually carried out in a solvent such as

Finally, the acyl group can also be treated with dimethylformamide, pyridine, hexamethylphosphoric triamide, di-with an iminohalogenating agent (e.g. phosphorus oxychloride oxane or another solvent that does not react etc.) and an imino etherifying agent, e.g. a low- adversely affected.

alkanol (such as methanol, ethanol, etc.) are treated, 35 if the compound (Ih) in the form of the free acid ver-man is followed by hydrolysis if necessary. is used, the reaction is preferably carried out in

The reaction temperature is not critical. According to a base, e.g. an inorganic base or an organic type of protective group for the amino group and the above-mentioned base, as selected above in connection with the aforementioned elimination method. The re-cleavage of the acylamino group was carried out, the action is preferably carried out under mild conditions, for example the reaction temperature is not critical. The reaction is carried out with cooling or at a slightly elevated temperature, preferably with cooling, at ambient temperature. or done with heating.

The invention also encompasses those cases in which one of the above-mentioned reactions and / or post-treatment-protected carboxy group into the free carboxy group during the treatment stages of the process according to the invention can only partially react the above-mentioned tautomeric isomers into others Procedure is converted. tautomeric isomers are converted. These cases should also

The new compounds (Ih) or salts thereof can be hereby encompassed within the scope of the present invention by becoming a compound (Ii) obtained.

a salt thereof undergoes cleavage of the ester group. In the aforementioned reactions and / or after-treatment

Suitable salts of the compounds (Ii) are e.g. The acidification stages of the process according to the invention can include the addition salts, as they have occasionally become partially mentioned with regard to the compound (II) above-mentioned syn- or anti-isomers. or be completely converted into other isomers. This too

The cleavage of the ester group can be accomplished by hydrolysis or cases within the scope of the present invention for reduction. will be closed.

The hydrolysis is preferably carried out in the presence of a base 55 when the new compound (I) is in the form of the free acid in or an acid. Suitable bases are e.g. anor- 4-position is obtained and / or if the new compound ganic bases and organic bases, such as those in the cleavage (I) has a free amino group, then it can be named after the conventional acylamino group R3. methods converted into their pharmaceutically acceptable salt

Suitable acids are e.g. organic acids (e.g. ami are converted.

sensic acid, acetic acid, propionic acid etc.) and inorganic acid processes for the preparation of the starting compounds (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid etc.). the explained in more detail below.

The reduction can e.g. of 2-iodoethyl ester, the starting compounds (purple) can be prepared

2,2,2-trichloroethyl ester or the like can be used. Talks in which a compound (VII) or a reactive derivative is applicable to the ductions which may be applicable for the elimination reaction according to the inventors of the amino group or a salt thereof with an amino protection are, for example a reduction with 65 means is implemented. The starting compounds (IUe) can be produced in a combination of a metal (for example zinc, zinc amalgams, by the compounds (III) or etc.) or a chromium salt compound (for example chromium (II) chloride), their reactive derivatives on the amino group or salts thereof (chromium (II) acetate etc.) and an organic or inorganic with an amino protective agent.

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Suitable reactive derivatives on the amino group of the compounds (VII) and Illh) and suitable salts of the compounds (VII) and (Illh) are e.g. those as described above with regard to the reactive derivatives on the amino group of the compounds (II) and salts of the compounds (II).

Suitable amino protecting groups are e.g. Alkylating agents and the like.

Suitable acylating agents are e.g. aliphatic, aromatic and heterocyclic isocyanates and the corresponding isothiocyanates and aliphatic, aromatic and heterocyclic carboxylic acids and the corresponding sulfonic acids, carboxylic acid esters and carbamic acids as well as the corresponding thio acids and the reactive derivatives of the abovementioned acids.

Suitable reactive derivatives of the above acids can include the same ones as were explained in more detail above with regard to the “reactive derivatives on the carboxy group of the compounds (III)”. The examples of protecting groups which can be introduced into the amino group of the compounds (VII) and (Illh) with the above-mentioned amino protecting group agents may be the same as those mentioned above in the explanation of the protecting groups for "protected amino groups".

The reaction can be carried out in a manner similar to the reaction of the compound (II) or its reactive derivative on the amino group or its salt with a compound (III) or its reactive derivative on the carboxy group.

The starting compounds (Illb) can be prepared by oxidizing the compounds (Illa).

The oxidation reaction can be carried out by conventional methods which are used to convert the so-called activated methylene group into a carbonyl group. So then the oxidation, for example, using conventional oxidizing agents, e.g. selenium dioxide, tri-well manganese compounds (e.g. manganese (III) acetate and potassium permanganate etc.) or the like. The oxidation is usually carried out in a solvent which does not adversely affect the reaction, e.g. of water, dioxane, tetrahydrofuran and the like.

The reaction temperature is not critical and the reaction is preferably carried out with heating to heating.

The starting compounds (IIIc) can be prepared by subjecting the compounds (Mb) to an elimination reaction of the carboxy protecting group. The starting compounds (Ille) can be prepared by subjecting the compounds (Ulf) to an elimination reaction of the carboxy protecting group. The starting compounds (Illh) can be prepared by subjecting the compounds (Illg) to an elimination reaction of the carboxy protecting group.

The elimination reaction can be carried out in a manner similar to that described above for the carboxy protecting group elimination reaction.

The starting compounds (IIld) can be prepared by reducing the compounds (IIIc). The reduction can be carried out as follows:

The reduction can be done by conventional methods, for example using an alkali metal borohydride (e.g. sodium borohydride, potassium borohydride, etc.) or the like. The reduction is usually carried out in a solvent which does not adversely affect the reaction, e.g. in water, methanol, ethanol, tetrahydrofuran, dioxane and the like. The reduction can also be carried out in the presence of an inorganic or organic base, e.g. an alkali metal (such as sodium, potassium, etc.), an alkaline earth metal (such as

Magnesium, calcium etc.), a hydroxide or carbonate or bicarbonate thereof, a tri (lower) alkylamine (e.g. trimethylamine, triethylamine etc.), picoline, N-methyl-pyrrolidine, N-methylmorpholine, l, 5-diazabicyclo - [4,3,0] -non-5 5-ene, 1,4-diazabicyclo- [2,2,2] -octane, 1,8-diazabicyclo- [5,4,0] -undecen-7 or the like can be performed.

The reaction temperature is not critical and the reaction is preferably carried out under mild conditions, for example with cooling or slight heating. 10 The starting compounds (IIle) can be prepared by reacting compounds (IIIc) with compounds (IV) or a salt thereof. The starting compounds (Ulf) can be prepared by reacting the compounds (IIIb) with compounds (IV) or a salt thereof.

The reaction can be carried out as follows: The reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol, etc.) or any other solvent which does not adversely affect the reaction.

The reaction is preferably carried out in the presence of a base, for example an inorganic base, such as an alkali metal (e.g. sodium, potassium etc.), alkaline earth metal (e.g. magnesium, calcium etc.), the hydroxide or carbonate or bicarboxylate thereof or the like or one organic base, e.g. an alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide etc.), a trialkylamine (e.g. trimethylamine, triethylamine etc.), N, N-dialkylaniline (e.g. N, N-dimethylaniline etc.), pyridine or the like. 30 The reaction temperature is not critical and the reaction is usually carried out with cooling or heating.

The starting compounds (Illg) can be prepared by reacting the compounds (Vm) with thiourea 35. The reaction can be carried out as follows: The reaction is usually carried out in a solvent such as water, an alcohol (for example methanol, ethanol, etc.), benzene, dimethylformamide, tetrahydrofuran or any other solvent which does not adversely affect the reaction. carried out.

The reaction temperature is not critical and the reaction is usually carried out from ambient to elevated temperature.

The new compounds (I) and their pharmaceutically acceptable salts have high antibacterial activity and inhibit the growth of a number of microorganisms including gram-positive and gram-negative bacteria. In particular, the synisomers of the new compounds (I) and their pharmaceutically acceptable salts 50 generally exhibit significantly higher antibacterial activity than the corresponding antiisomers of the new compounds (I) and the pharmaceutically acceptable salts thereof. For therapeutic purposes, the new compounds can be used in the form of drugs which contain the compounds as active ingredients in admixture with pharmaceutically acceptable carriers, e.g. contain organic or inorganic solids or liquid excipients suitable for oral, parenteral or external administration. The drugs can e.g. Capsules, tablets, dragees, ointments or 60 suppositories, solutions, suspensions, emulsions and the like. If desired, the preparations can also contain auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other customary additives.

65 The dosage of the compounds varies according to the age and condition of the patient. An average single dose of about 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the new compounds has been found to be effective

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10th

Treatment of infectious diseases caused by pathogenic bacteria has been proven.

The antimicrobial activities of some representative compounds of the formula I against some test strains of pathogenic bacteria are shown below on the basis of their minimal inhibitory concentrations.

Test method:

In vitro antibacterial activity was determined by the two-fold agar plate dilution method described below.

The loop content of an overnight culture of the individual test strains in trypticase soy broth (108 viable cells per ml) was coated on cardiac infusion agar (HI agar), which contains graded concentrations of the representative

Test results:

contained test compounds. The minimum inhibitory concentration (MIC) was expressed as | i g / ml after 20 hours of incubation at 37 ° C.

5 test connections:

(1) 2-methyl-7- [2- (2-aminothiazol-4-yl) glyoxylamido] -3-cephem-4-carboxylic acid (test compound (1))

(2) 2-methyl-7- [2-hydroxy-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (test compound (2))

io (3) 2-methyl-7- [2-methoxyimino-2- (2-aminothiazole) -4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres) (test compound (3))

(4) Pivaloyloxymethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate 15 (Synisomeres) (test compound (4)).

organism

Test ver

Test procedure

Test ver

Test ver

binding (1) binding (2)

binding (3)

binding (4)

E. Coli No. 324

0.78

0.78

0.05

0.2

No. 341

0.2

0.39

0.2

0.78

Class No. 417

0.39

0.39

0.2

0.2

Arogenic No. 418

0.39

0.78

0.1

0.78

No. 427

0.1

0.39

0.05

0.2

No. 428

0.78

1.56

0.2

1.56

Pr. Minabilis No. 501

0.78

1.56

0.05

0.2

No. 520

0.39

1.56

0.05

0.1

No. 525

6.25

1.56

0.05

0.2

The invention is illustrated in the examples.

Establishing the output connections:

Production Example 1

(a) A mixture of 2,2,2-trichloroethyl-2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (0.38 g), trimethylsilyl acetamide (1.1 g) and methylene chloride ( 10 ml) was stirred for 30 min at room temperature. The solution thus obtained was cooled to -15 ° C. To the solution was added dropwise 3-oxo-4-bromobutyryl bromide (1.0 mmol) in carbon tetrachloride (13 ml) with cooling to -15 ° C. The mixture was stirred at the same temperature for 1.5 hours and without external cooling for 30 minutes. The mixture was poured into cold water. The organic layer was then separated. The organic layer was washed with 2N hydrochloric acid (8 ml X 3) and water (10 ml X 2) in order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was pulverized in diisopropyl ether, collected by filtration, and then dried to give a light brown powder of 2,2,2-trichloroethyl-2-methyl-7- (3-oxo-4-bromobutyramido) -3-cephem-4 carboxylate (0.31 g), mp 78 to 83 ° C (dec.), was obtained.

IR spectrum (Nujol)

3320.1785.1735.1675.1284.1210 cm-1.

NMR spectrum (CDC13, ô)

1.54 (3H, d, J = 7Hz)

3.65 (1H, m)

3.76 (4 / 5H, s)

4.11 (6 / 5H, s)

4.90 (2H, s)

5.00 (1H, d, J = 6Hz)

5.95 (1H, m)

6.72 (lH, d, J = 6.8Hz)

7.05 (2 / 5H, d, J = 9Hz)

7.73 (3 / 5H, d, J = 9Hz).

In a similar manner, p-nitrobenzyl-2-methyl-7- (3-oxo-4-bromobutyramido) -3-cephem-4-carboxylate was obtained in the form of a powder.

IR spectrum (Nujol)

3270.1780.1725.1655.1625.1600 cm ~ 1

40 NMR spectrum (D6-dimethyl sulfoxide, ô)

ppm 1.79 (3H, d, J = 6.5Hz)

3.67 (2H, s)

3.7-4.2 (1H, m)

4.43 (2H, s)

45 5.13 (lH, d, J = 4.5Hz)

5.43 (2H, s)

5.87 (1H, dd, J = 4.5 and 8Hz)

6.76 (1H, d, J = 6.5 Hz)

7.73 (2H, d, J = 9Hz)

50 8.26 (2H, d, J = 9Hz)

9.13 (1H, d, J = 8Hz)

(b) To a solution of 2,2,2-trichloroethyl-2-methyl-7- (3-oxo-4-bromobutyramido) -3-cephem-4-carboxylate (2.54 g) in 55 glacial acetic acid (25 ml ), a solution of sodium nitrite hydrate (0.33 g) in water (1 ml) was added dropwise over 3 minutes with stirring at 10 to 15 ° C. The mixture was stirred at the same temperature for 1 hour. After pouring the reaction mixture into cold water (70 ml), the precipitate formed was collected by filtration and then dried, whereby a brown powder of 2,2,2-trichloroethyl-2-methyl-7- (2- hydroxyimino-3-oxo-4-bromobutyr-amido) -3-cephem-4-carboxylate (a mixture of syn and anti-isomers) (2.0 g), mp 76 to 80 ° C (dec.).

65

IR spectrum (Nujol):

1670 to 1710.1540.1280.1215.715 cm "\

NMR spectrum (d6-dimethyl sulfoxide, ô)

1.44 (3H, d, J = 7Hz)

3.2 to 3.8 (2H, broad)

3.91 (IH, m)

4.57 (IH, s)

5.02 (2H, s)

5.16 (1H, d, J = 5Hz)

5.91 (1H, dd, J = 5 and 9Hz)

6.74 (1H, d, J = 6.5Hz)

9.32 (1H, d, J = 9Hz).

The p-nitrobenzyl-2-methyl-7- (2-hydroxyimino-3-oxo-4-bromobutyramido) -3-cephem-4-carboxylate (syn isomer) was obtained in a similar manner.

IR spectrum (Nujol)

3260.1775, 1725, 1700, 1660, 1630, 1600 cm "1

NMR spectrum (D6-dimethyl sulfoxide, ô)

ppm 1.45 (3H, d, J = 7Hz)

3.6-4.2 (lH, m)

4.6 (2H, s)

5.17 (1H, d, J = 5Hz)

5.43 (2H, s)

5.98 (1H, dd, J = 5 and 9Hz)

6.77 (1H, d, J = 7Hz)

7.73 (2H, d, J = 9Hz)

8.27 (2H, d, J = 9Hz)

9.37 (1H, d, J = 9Hz)

13.32 (1H, s)

Production Example 2

To a solution of 2,2,2-trichloroethyl-2-methyl-7- (2-hydroxyimino-3-oxo-4-bromobutyramido) -3-cephem-4-carboxylate (a mixture of syn and anti isomers) (1 , 2 g) in ethanol (20 ml), a solution of diazomethane (0.1 mol) in diethyl ether was added dropwise with stirring and ice-cooling to complete the reaction. After concentrating the reaction mixture under reduced pressure, the residue was pulverized in diisopropyl ether, collected by filtration, and dried to give a brown powder of 2,2,2-trichloroethyl-2-methyl-7- (2-methoxyimino-3-oxo-4 -bromobutyramido) -3-cephem-4-carboxylate (a mixture of syn and anti isomers) (1.1 g), mp 80 to 83 ° C (dec.).

IR spectrum (Nujol):

3300.1785, 1737, 1650 to 1710.1535, 1280, 1210, 1160, 1045.715 cm ~ K

NMR spectrum (d6-dimethyl sulfoxide, Ô)

1.46 (3H, d, J = 7Hz)

4.0 (1H, m)

4.04 (3H, s)

4.62 (1H, s)

5.05 (2H, s)

5.29 (1H, d, J = 5Hz)

5.95 (lH, m)

6.74 (lH, m)

9.48 (1H, d, J = 9Hz).

Production Example 3

(a) Formic acid (169.2 ml) was added dropwise to acetic anhydride (384 ml) over the course of 15 to 20 minutes and while cooling to 35 ° C. The mixture was stirred at 55 to 60 ° C for 1 h. To the mixture was added ethyl 2- (2-ami-nothiazol-4-yl) acetate, which is also referred to as ethyl 2- (2-imino-2,3-dihy-drothiazol-4-yl) acetate can, (506 g) in

11 634 074

Given over 15 to 20 min with ice cooling and stirring. The mixture was stirred at room temperature for 1 hour. After the reaction, the solvents were distilled off. Isopropyl ether (2500 ml) 5 was added to the residue and the mixture was stirred at room temperature for 1 h. The precipitates were collected by filtration, washed with diisopropyl ether and then dried to give ethyl 2- (2-formylaminothiazol-4-yl) acetate, also known as ethyl 2- (2-formylimino-2,3-dihydrothi -ioazol-4-yl) acetate (451.6 g), mp 125 to 126 ° C. The remaining filtrate was concentrated and the residue was washed with diisopropyl ether (500 ml) and dried to give an additional amount of the same compound (78.5 g).

15

IR spectrum (Nujol):

1737.1700 cm-1.

NMR spectrum (CDC13, Ô):

201.25 (3H, t, J = 8Hz)

3.7 (2H, s)

4.18 (2H, q, J = 8Hz)

6.9 (1H, s)

8.7 (1H, s).

25th

(b) A mixture of manganese (III) acetate tetrahydrate (120 g), acetic acid (1000 ml) and acetic anhydride (100 ml) was stirred in an oil bath at 130 to 135 ° C for 20 min. Potassium permanganate (20 g) was added to the mixture over 5 minutes at 105 to 110 ° C with stirring. The mixture was then stirred at 130 to 135 ° C for a further 30 min. The mixture was cooled to room temperature and the mixture was treated with ethyl 2- (2-formylaminothiazol-4-yl) acetate, also known as ethyl 2- (2-formylimino-2,3-dihydrothiazol-4-yl) - 35 acetate can be designated, (53.5 g) added. The mixture was then stirred at 38 to 40 ° C for 15 hours while introducing air at a rate of 6000 ml per min. After the reaction, the precipitates were collected by filtration. The precipitates were washed successively with acetic acid-40 re and water and then dried, whereby ethyl 2- (2-formylaminothiazol ~ 4-yl) -glyoxylate was obtained, which was also called ethyl 2- (2-formylimino-2,3) -dihydrothiazol-4-yl) glyoxylate (41.5 g), mp 232 to 233 ° C (dec.).

45 (c) To a suspension of ethyl 2- (2-formylaminothi-azol-4-yl) glyoxylate, which is also called ethyl 2- (2-formylimino-2,3-dihydrothiazol-4-yl) glyoxylate (281 g) in water (1100 ml) was added an aqueous IN sodium hydroxide solution (2,231) with stirring and ice cooling. The mixture was then stirred at 10 to 15 ° C. for 5 min. After filtering the reaction mixture, the filtrate was adjusted to a pH of 1 with concentrated hydrochloric acid with stirring. The precipitates were collected by filtration, washed with water and then dried to give 55 2-2- (formylaminothiazol-4-yl) glyoxylic acid, which was also called 2- (2-formylimino-2,3-dihydrothiazol-4- yl) -gly-oxyacid can be called (234 g), mp 133 to 136 ° C (dec.).

60 NMR spectrum (NaDC03, ò):

8.27 (IH, s)

8.6 (IH, s).

Production Example 4 65 To a suspension of 2- (2-formylaminothiazol-4-yl) glyoxylic acid, which can also be referred to as 2- (2-formylimino-2,3-dihydrothi-azol-4-yl) glyoxylic acid, ( 20 g) in water (400 ml) became sodium bicarbonate (8.4 g) under ice cooling

634 074

12

and stirring. The mixture was stirred at the same temperature for 10 minutes and then ethanol (10 ml) was added. To the mixture was added sodium borohydride (1.52 g) over 10 minutes while stirring at the same temperature, and the mixture was stirred at the same temperature for 1 hour and 50 minutes. After the reaction, the reaction mixture was filtered. The filtrate was adjusted to pH 4.0 with 10% hydrochloric acid and then concentrated under reduced pressure until the volume was 100 ml. The concentrated filtrate was adjusted to pH 1 with 10% hydrochloric acid and the crystallization was started by scratching. The concentrated filtrate was stirred at room temperature for 1 hour and then left in a refrigerator overnight. The precipitates were collected by filtration, washed twice with ice water and then dried under suction to give 2-hydroxy-2- (2-formylaminothiazol-4-yl) acetic acid, also known as 2-hydroxy-2- (2- formylimino-2,3-dihydrothiazol-4-yl) acetic acid can be called (14.8 g), mp 188 to 189 ° C (dec.), was obtained.

IR spectrum (Nujol):

1730.1635 cm-1.

NMR spectrum (NaDC03, Ô):

5.07 (lH, s)

7.15 (1H, s)

8.5 (1H, s).

Production Example 5

(a) A solution of ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (17.4 g) and thiourea (5.4 g) in ethanol (100 ml) was washed for 4 hours Reflux heated. The reaction mixture was left in a refrigerator, whereby crystals were precipitated. The crystals were collected by filtration, washed with ethanol and dried to give ethyl 2-methoxyimino-2- (2-aminothiazol-4-yl) acetate hydrobromide (anti-isomer) (9.5 g). The filtrate and washings were combined and concentrated under reduced pressure. Water (100 ml) was added to the residue and the mixture was washed with ether. The aqueous layer was made alkaline with a 28% aqueous ammonia solution and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give crystalline ethyl 2-methoxyimino-2- (2-aminothiazol-4-yl) acetate (Synisomeres), which is also called ethyl 2-methoxyimino-2- (2-imino-2 , 3-dihydrothiazol-4-yl) acetate (Synisomeres), (5.2 g) was obtained.

IR spectrum (Nujol):

3400.3300.3150.1725.1630.1559 cm ~ K

NMR spectrum (CDC13, ö):

1.38 (3H, t, J = 7Hz (

4.03 (3H, s)

4.38 (2H, q, J = 7Hz)

5.91 (2H, broad s)

6.72 (1H, s).

(b) Ethanol (10 ml) became a suspension of ethyl 2-methoxyimino-2- (2-aminothiazol-4-yl) acetate (Synisomeres), also known as ethyl 2-methoxyimino-2- (2- imino-2,3-dihydro-thiazol-4-yl) acetate (Synisomeres) can be referred to (2.2 g) in an IN aqueous sodium hydroxide solution (12 ml). The mixture was stirred at ambient temperature for 15 h. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid. Ethanol was distilled off under reduced pressure. The remaining aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling, whereby crystals were precipitated. The crystals were collected by filtration, washed with acetone and recrystallized from ethanol, giving colorless needles of 2-methoxyimino-2- (2-aminothiazol-4-yl) acetic acid (Syniso-îomeres), also known as 2-methoxyimino-2 - (2-imino-2,3-dihydro-thiazol-4-yl) acetic acid (Synisomeres) can be called (1.1 g) were obtained.

IR spectrum (Nujol):

15 3150.1670.1610.1585 cm "l.

NMR spectrum (d6-dimethyl sulfoxide, ô):

3.83 (3H, s)

6.85 (IH, s)

207.20 (2H, broad s).

Production Example 6

Pyridine (5 ml) was converted into a suspension of 2-methoxyimino-2- (2-aminothiazol-4-yl) acetic acid (Synisomeres), which was also called 2-methoxyimino-2- (2-imino-2, 3-dihydrothiazol-4-yl) acetic acid (Synisomeres) can be referred to (2.0 g) in ethyl acetate (20 ml). A solution of bis (2,2,2-tri-fluoroacetic acid) anhydride (2.5 g) in ethyl acetate (3 ml) was added dropwise with stirring at 5 to 7 ° C and the mixture was stirred at 3 for 30 min stirred up to 5 ° C. Water (30 ml) was added to the reaction mixture and the ethyl acetate layer was separated. The aqueous layer was further extracted with ethyl acetate. The two layers of ethyl acetate were combined, washed with water and a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 2-methoxyimino-2- [2- (2,2,2-trifluoroacetylamino) thiazol-4-yl] acetic acid (synisomer), also known as 2-methoxyimino-2 - [2- (2,2,2-trifluoroacetylimino) -2,3-dihydro-40 thiazol-4-yl] acetic acid (Synisomeres) (0.72 g) was obtained.

IR spectrum (Nujol):

1725.1590 cm "\

45

NMR spectrum (d6-dimethyl sulfoxide, ö):

3.91 (3H, s)

7.68 (1H, s).

50 The following connections were made in a similar manner:

i) 2-methoxyimino-2- (2-formylaminothiazol-4-yl) acetic acid (synisomer), which is also known as 2-methoxyimino-2- (2-formyl-imino-2,3-dihydrothiazol-4-yl ) -acetic acid (Synisomeres) -55, mp 152 ° C (dec.).

IR spectrum (Nujol):

3200.2100 to 2800.1950.1600 cm "'.

60 NMR spectrum (d6-dimethyl sulfoxide, ö):

3.98 (1H, s)

7.62 (1H, s)

8.60 (1H, s).

65

example 1

To dimethylformamide (0.54 g) was added dropwise phosphorus oxychloride (1.13 g) with stirring and ice cooling, and the mixture was stirred at 40 ° C for 30 minutes. Then it was

13

634 074

de dried ethyl acetate (13 ml) was added. The mixture gradually became 2- (methoxyimino-2- (2-trifluoroacetylamino-thiazol-4-yl) acetic acid (Synisomeres), also known as 2-meth-oxyimino-2- (2-trifluoroacetylimino-2,3-dihydrothiazole -4-yl) -es-acetic acid (Synisomeres) (2.0 g) was added with cooling to 3 to 5 ° C. The mixture was stirred at the same temperature for 40 min while cooling to - 25 ° to - 20 ° C with stirring to a solution which had been prepared by a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid (1.44 g) and trimethylsilylacetamide (9.78 g) in dried ethyl acetate (30 ml) was stirred for 5 to 10 min at 35 to 40 ° C. The mixture was stirred at the same temperature for 1 h, cold water was added with ice-cooling, after which the mixture became about 5 min at the same temperature, the ethyl acetate layer was separated from the reaction mixture, and the remaining aqueous layer was washed with ethyl acetate (20 ml X 2) extracted. The ethyl acetate layers were combined, washed with water and then water (50 ml) was added. The mixture was adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate solution with ice cooling and stirring. The aqueous layer was separated. After washing the aqueous layer with ethyl acetate, ethyl acetate (70 ml) was added. The mixture was adjusted to pH 2.5 with 10% hydrochloric acid with ice cooling and stirring. The ethyl acetate layer was separated from the mixture and the remaining aqueous layer was extracted with ethyl acetate (30 ml). The ethyl acetate layers were combined, washed with an aqueous sodium chloride solution, dried and then concentrated to a total volume of about 10 ml. To the residue was added diethyl ether (20 ml) and the mixture was stirred for 1 hour. The precipitates were collected by filtration, washed with diethyl ether and then dried to give 2-methyl-7- [2-meth-oxyimino-2- (2-trifluoroacetylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), also known as 2-methyl-7- [2-methoxyimino-2- (2-trifluoroacetylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres) can, (2.2 g), mp 197 to 198 ° C (dec.) was obtained. The remaining filtrate was concentrated. The residue was washed with diethyl ether and then dried, whereby the same compound (0.3 g) was obtained.

IR spectrum (Nujol):

3270.1788.1730.1660 cm-1.

NMR spectrum (d6-dimethyisulfoxide, Ô):

1.46 (3H, d, J = 8Hz, 2-CH3)

3.7 to 4.0 (1H, m, 2-H)

3.95 (3H, s, OCH3)

5.17 (IH, d, J = 6Hz, 6-H)

5.94 (1H, d, d, J = 6 and 7Hz, 7-H)

6.62 (IH, d, J = 6Hz, 3-H)

7.56 (1H, s, 5-H on the thiazole ring)

9.81 (IH, i.e. J = 7Hz, 7-CONH).

Example 2

To dimethylformamide (78 ml) was added dropwise phosphorus oxychloride (11.9 g) with stirring and ice cooling. The mixture was stirred at 40 ° C for 30 min. To the mixture was added 2- (2-formylaminothiazol-4-yl) glyoxylic acid, which can also be called 2- (2-formylimino-2,3-dihydrothiazoI-4-yl) glyoxylic acid, (7.8 g) given with cooling to - 20 ° C. The mixture was then stirred for 30 minutes while cooling to -20 to -15 ° C. The mixture thus obtained was stirred and cooled to -50 to -45 ° C

to a solution prepared in such a way that a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid (8.35 g) and bis- (trimethylsilyl) -acetamide (19.5 ml) was stirred in dried methylene chloride (170 ml) at room temperature. The mixture was at -45 to for 1 h

- 40 ° C and then the reaction mixture was poured into a solution of sodium bicarbonate (32 g) in water (1.51) with shaking. The aqueous layer was separated and washed with ethyl acetate. The aqueous layer io was layered with ethyl acetate and then adjusted to a pH of 1 to 2 with concentrated hydrochloric acid. The ethyl acetate layer was separated from the mixture and the remaining aqueous layer was extracted with ethyl acetate (200 ml X 2). The ethyl acetate layers were combined with one another, washed with water and then concentrated to a small volume. The precipitates were collected by filtration, washed with a small amount of ethyl acetate and then dried to give 2-methyl-7- [2- (2-formylaminothiazol-4-yl) glyoxylamido] -3-cephem-4-carbon-20 acid, which can also be called 2-methyl-7- [2- (2-formylimino-2,3-dihydro-thiazol-4-yl) glyoxylamido] -3-cephem-4-carboxylic acid, (7.9 g), mp 210 to 215 ° C (dec.), was obtained.

25 IR spectrum (Nujol): 3300, 3150, 1780, 1713, 1660, 1625, 1533 cm "K

NMR spectrum (d6-dimethyl sulfoxide, ô):

1.45 (3H, d, J = 7Hz, 2-CH3)

30 3.7 to 4.1 (1H, m, 2-H)

5.17 (1H, i.e. J = 5Hz, 6-H)

5.91 (1H, dd, J = 5 and 8Hz, 7-H)

6.59 (1H, d, J = 6Hz, 3-H)

8.40 (1H, s, 5-H on the thiazole ring)

35 8.57 (1H, s, OHC-N =)

9.83 (1H, d, J = 8Hz, 7-CONH).

Example 3

To a solution of thionyl chloride (3.01 g) in methylene chloride (45 ml) was added dimethylformamide (0.928 g) and 2- (2-formylaminothiazol-4-yl) glyoxylic acid, also known as 2- (2-formylimino -2,3-dihydrothiazol-4-yl) glyoxylic acid can be given (3.71 g). The mixture was stirred at room temperature for 4 hours. The mixture obtained in this way was stirred and cooled to −25 to

- 20 ° C to a solution which had been prepared by mixing a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid (3.3 g) and trimethylsilylacetamide (16.2 g) in methylene chloride ( 60 ml) stirred for 40 min at room temperature

Had turned 50. The mixture was stirred at -25 to -20 ° C for 30 minutes, at -10 to 0 ° C for 30 minutes and then at room temperature for 30 minutes. Water (30 ml) was added to the reaction mixture and the mixture was stirred for 10 minutes. After a saturated aqueous sodium bicarbonate solution was added to the mixture to dissolve the precipitates, the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the mixture was adjusted to pH 2 with 2N hydrochloric acid. The ethyl acetate layer was then separated off; the remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated. The crystalline residue thus obtained was pulverized in diethyl ether, collected by filtration, and then dried to give yellow crystalline powder of 2-methyl-7- [2- (2-formylaminothiazol-4-yl) glyoxylamido] -3 -cephem-4-carboxylic acid, also known as 2-methyl-7- [2- (2-formylimino-2,3-dihydrothiazole-

634 074

4-yI) -glyoxylamido] -3-cephem-4-carboxylic acid can be called (3.81 g) was obtained.

IR spectrum (Nujol):

3475,3315,3200,1788,1655,1620,1530,1293,1240,1185 cm-1.

NMR spectrum (d6-dimethyl sulfoxide, ô):

1.48 (3H, d, J = 7Hz)

3.70 to 4.17 (lH, m)

5.21 (1H, d, J = 5Hz)

5.96 (1H, d, J = 5Hz)

6.63 (1H, d, J = 6Hz)

8.44 (1H, s)

8.62 (1H, s).

Example 4

Phosphorus oxychloride (12.5 g) was added dropwise to dimethylformamide (6.42 g) over the course of 20 min with stirring and cooling to 5 to 10 ° C. The mixture was stirred at 40 ° C for 30 minutes and then ethyl acetate (200 ml) was added with vigorous stirring. After cooling the mixture to 3 ° C, 2-methoxyimino-2- (2-formyl-aminothiazol-4-yl) -acetic acid (Synisomeres), also known as 2-methoxyimino-2- (2-formylimino-2,3 -dihydrothiazol-4-yl) -acetic acid (Synisomeres) can be designated (18.34 g) and the mixture was then stirred at 3 to 5 ° C for 40 min. The resulting solution was added to a solution prepared by stirring a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid (17.1 g) with vigorous stirring and cooling to -25 ° C. and trimethylsilylacetamide (84 g) in ethyl acetate (300 ml) was stirred at room temperature for 1 h. The mixture was stirred at -20 to -15 ° C for 1 hour and at -10 to -5 ° C for 30 minutes. Water (200 ml) at room temperature was added to the mixture, and the mixture was stirred at the same temperature for an additional 30 minutes. After adding a saturated aqueous solution of sodium bicarbonate to the mixture to dissolve the precipitates, the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the mixture was adjusted to pH 2 with 2N hydrochloric acid. The ethyl acetate layer was then separated. The remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, treated with activated carbon, and then concentrated. The crystalline residue thus obtained was pulverized in diethyl ether, collected by filtration and then dried, whereby white crystals of 2-methyl-7- [2-meth-oxyimino-2- (2-formylaminothiazol-4-yl) -acetamido] -3 -ce-phem-4-carboxylic acid (synisomeres), also known as 2-methyl-7- [2-methoxyimmo-2- (2-formylimmo-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem -4-carboxylic acid (Synisomeres) can be called (32.2 g) were obtained. This compound was recrystallized from methanol, whereby white crystals of the pure compound, mp 174 to 204 ° C. (dec.), Were obtained.

IR spectrum (Nujol):

3270.1780.1655.1285.1040 cm-1.

NMR spectrum (d6-dimethyl sulfoxide, ô):

1.44 (3H, d, J = 7Hz)

3.68 to 4.12 (lH, m)

3.90 (3H, s)

5.14 (1H, d, J = 5Hz)

5.90 (1H, d, J = 5Hz)

6.56 (1H, d, J = 6Hz)

14

7.40 (1H, s)

8.50 (1H, s).

The following compounds 5 were prepared in a similar manner:

1) 2-Methyl-7- [2-hydroxy-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, which is also known as 2-methyl-7- [ 2-hydroxy-2- (2-imino-2,3-dihydrothiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid hydrochloride can be referred to, mp> 250 ° C.

2) 2-Methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), also known as 2-methyl-7- [2- methoxyimino-2- (2-imino-2,3-dihydrothi-azol-4-yl) acetamido] -3-cephem-4-carboxylic acid (synisomeres)

15, Zp> 241 ° C.

3) 2-methyl-7- [2-aminothiazol ~ 4-yl) -glyoxylamido] -3-cephem-4-carboxylic acid hydrochloride, which is also known as 2-methyl-7- [2- (2-imino- 2,3-dihydrothiazol-4-yl) -glyoxylamido] -3-ce-phem-4-carboxylic acid hydrochloride, mp

20> 270 ° C.

4) 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres) which is also known as the 2nd , 2,2-Trichloroethyl-2-methyl-7- [2-meth-oxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-

25 cephem-4-carboxylate (Synisomeres) can be called, mp 128 to 149 ° C (dec.).

5) Pivaloyloxymethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres), which is also known as pivaloyloxymethyl-2-methyl- 7- [2-meth-

30oxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) -acetamido] -3-cephem-4-carboxylate (Synisomeres), mp 165 to 170 ° C (dec.).

6) p-nitrobenzyl-2-methyl-7- [2-hydroxyimino-2- (2-ami-nothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn isome-

35 res), which is also known as p-nitrobenzyl-2-methyl-2- [2-hydroxyimino-2- (2-immo-2,3-dihydrothiazol-4-yl) acetamido] -3-ce-phem- 4-carboxylate (syn isomer) can be prepared; powder product.

7) 2-methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) -

40 acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isome-res) can be represented.

8) 2-methyl-7- [2-ethoxyimino-2- (2-formylaminothiazole-4-

45 yl) -acetamido] -3-cephem-4-carboxylic acid (syn-isomer), which is also known as 2-methyl-7- [2-ethoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl ) acetamido] -3-cephem-4-carboxylic acid (syn-isomer) can be represented.

50 IR spectrum (Nujol): 3350.3240.3190.1775.1700.1650.1620 cm "1

NMR spectrum (D6-dimethyl sulfoxide, ô):

I, 28 (3H, t, J = 7Hz)

55 1.47 (3H, d, J = 8Hz)

3.68-4.2 (lH, m)

4.18 (2H, q, J = 7Hz)

5.15 (1H, d, J = 5Hz)

5.94 (1H, d, d, J = 5 and 8Hz)

60 6.58 (1H, d, J = 6Hz)

7.40 (lH, s)

8.52 (1H, s)

9.65 (lH, d, J = 8Hz)

II, 64 (1H, broad s)

65

9) 2-methyl-7- [2-isopropoxyimino-2- (2-formylaminothi-azol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl 7- [2-isopropoxyimino-2- (2-for-

mylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-car-bonic acid (syn-isomer) can be represented.

IR spectrum (Nujol):

3480.3300, 3180.1780.1740.1700.1660 cm "1

NMR spectrum (D6-dimethyl sulfoxide, ô):

1.14 (6H, d, J = 7Hz)

1.4 (3H, d, J = 6Hz)

3.8 (1H, m)

4.35 (1H, m)

5.1 (1H, d, J = 5Hz)

5.87 (1H, d, d, J = 5 and 8Hz)

6.5 (1H, d, J = 6Hz)

7.35 (1H, s)

8.45 (1H, s)

9.55 (1H, d, J = 8Hz)

10) 2-methyl-7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn isomer), which is also known as 2-methyl-7 - [2-ethoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn isomer) can be prepared.

IR spectrum (Nujol)

3350.1790.1730.1670.1630 cm ~ 1

11) 2-methyl-7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-isopropoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared.

IR spectrum (Nujol)

3350.1780.1670.1600 cm "1

12) 2-Methyl-7- [2-propoxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [ 2-propoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared.

IR spectrum (Nujol)

3450.3300, 3050, 1780, 1730, 1690, 1660 cm "1

NMR spectrum (D6-dimethyl sulfoxide, ô):

0.96 (3H, t, J = 6Hz), 1.48 (3H, d, J = 6Hz),

1.68 (2H, m), 3.85 (1H, m), 4.02 (2H, t, H = 6Hz),

5.14 (1H, d, J = 5Hz), 5.96 (1H, d, d, J = 5.9Hz),

6.6 (1H, d, J = 6Hz), 7.42 (1H, s), 8.56 (1H, s),

9.70 (1H, d, J = 9Hz)

13) 2-methyl-7- [2-propoxyimino-2 ~ (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-propoxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isome-res) can be prepared.

IR spectrum (Nujol)

3330, 3080, 1780, 1670 cm "1

14) 2-methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7 [ 2-hexyloxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isome-res) can be prepared.

15 634 074

IR spectrum (Nujol)

3300.3200.1780.1670.1630 cm-1

15) 2-Methyl-7- [2-hexyloxyimino-2- (2-formylaminothi-5 azol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer), which is also known as 2-methyl -7- [2-Hexyloxymino-2- (2-for-mylimino-2,3-dihydrothiazol-4-yl) acetamodo] -3-cephem-4-carboxylic acid (syn isomer) can be prepared.

io IR spectrum (Nujol)

3270.3180.1790.1700.1655 cm ~ 1

NMR spectrum (D6-dimethyl sulfoxide, ô)

0.6 to 2.1 (14H, m), 3.6 to 4.4 (3H, m), 5.15 (1H, d, J = 5), 15 5.93 (1H, d, d, J = 5, 8Hz), 6.57 (1H, d, J = 6), 7.40 (1H, s) 8.54 (1H, s), 9.62 (1H, d, J = 8 Hz) , 12.7 (1H, s)

16) 2-Methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hexanoyloxymethyl ester

20 (syn isomer), which also as 2-methyl-7- [2-hexyloxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid- hexanoyloxymethyl ester (syn isomer) can be represented.

25th

IR spectrum (Nujol)

3340.3200 (wide), 3150 (wide), 1790 (wide), 1750 to 1790, 1680.1630 cm-1

30 Example 5

A suspension of 2-methoxyimino-2- (2-aminothiazol-4-yl) acetic acid (Synisomeres), also known as 2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetic acid (Synisomeres) can be called (26 g) in ethyl acetate (250 ml) was cooled to 35 5 ° C and added dropwise with stirring and under ice cooling with phosphorus oxychloride (25 g). The mixture was then stirred at 4-6 ° C for 30 minutes. To the mixture was added dropwise a solution of trimethylsilylacetamide (22 g) in ethyl acetate (20 ml) with stirring and under ice cooling 40. The mixture was stirred at 4-6 ° C for 30 minutes. Additional phosphorus oxychloride (25 g) was then added with stirring and ice cooling. The mixture was stirred at the same temperature for 15 minutes and dimethylformamide (10.6 g) was added dropwise at the same temperature. 45 The mixture was stirred at the same temperature for 40 min. The resulting clear solution was cooled to -10 ° C. On the other hand, to a solution of 2-methyl-7-amino-3-cephem-4-carboxylic acid (23.9 g) in a solution of sodium bicarbonate (25 g) and water (400 ml) was added acetone (300 ml) and the mixture was cooled to -5 ° C. To the mixture was dropwise added the clear solution of -5 to 0 ° C prepared above, and then the mixture was stirred for 2 hours. The pH of the mixture was maintained at 6 with a 15% aqueous sodium 55 triumbicarbonate solution throughout. Insoluble materials were filtered off and the aqueous layer was separated. The aqueous layer was adjusted to pH 3 with 20% hydrochloric acid, and precipitated crystals were collected by filtration, washed with water and 60 acetone in order, and then dried under reduced pressure. In this way, 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), also known as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido J-3-cephem-4-65 carboxylic acid (Synisomeres) can be called (39.4 g). The compound was identified by IR and NMR analysis with the compound of Example 6.

The sodium or ammonium salt of this compound is said to

634 074

16

can be obtained in a conventional manner. The physical properties of these compounds are as follows:

1) sodium salt, powder:

IR spectrum (Nujol):

1770.1660.1560.1500 cm "!.

NMR spectrum (d6-dimethyl sulfoxide, ô):

1.37 (3H, d, J = 7.0Hz)

3.64 (1H, m)

3.84 (3H, s)

4.97 (1H, d, J = 5.0Hz)

5.74 (lH, m)

6.21 (1H, d, J = 6.0Hz)

6.70 (lH, s)

7.30 (2H, m)

9.63 (1H, m).

2) ammonium salt, powder:

IR spectrum (Nujol):

1775.1660.1580.1530 cm- K

NMR spectrum (d6-dimethyl sulfoxide, ô):

1.37 (3H, d, J = 7.0Hz)

3.64 (1H, m)

3.83 (3H, s)

4.99 (1H, d, J = 5.0Hz)

5.8 (5H, m)

6.17 (1H, d, J = 6.0Hz)

6.87 (1H, s)

7.27 (2H, m)

9.55 (1H, m).

Example 6

To a solution of sodium acetate (11.6 g) in water (43 ml) was added 2-methyl-7- [2-methoxyimino-2- (2-trifluoroacetyl-aminothiazol-4-yl) acetamido] -3-cephem- 4-carboxylic acid (synisomeres), which is also known as 2-methyl-7- [2-methoxyimino-2- (2-trifluoroacetylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-ce-phem- 4-carboxylic acid (Synisomeres), (2.1 g) was added with stirring and the mixture was adjusted to a pH of 6 with 5% aqueous sodium bicarbonate solution. The mixture was stirred at room temperature overnight. After the reaction, the reaction mixture was adjusted to pH 2.8 to 3 with 10% hydrochloric acid and then cooled. The precipitates were collected by filtration and then dried to give 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), which can also be referred to as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), ( 1.1g) was obtained, mp> 241 ° C. The same compound (0.25 g) was obtained from the filtrate in a conventional manner.

IR spectrum (Nujol):

3470.3320.3190.2380.1783.1690.1655.1622.1530 cm- K

NMR spectrum (d6-dimethyl sulfoxide, ô):

1.44 (3H, d, J = 8Hz, 2-CH3)

3.7 to 4.0 (1H, m, 2-H)

3.84 (3H, s, OCH3)

5.12 (1H, d, J = 6Hz, 6-H)

5.89 (1H, dd, J = 6 and 8Hz, 7-H)

6.57 (1H, d, J = 7Hz, 3-H)

6.77 (1H, s, 5-H on the thiazole ring)

9.62 (1H, d, J = 8Hz, 7-CONH).

Example 7

To a suspension of 2-methyl-7- [2- (2-formylamino-thiazol-4-yl) -glyoxylamido] -3-cephem-4-carboxylic acid, which is also aIs2-methyl-7- [2- (2- formylimino-2,3-dihydrothiazol-4-yl) -5 glyoxylamido] -3-cephem-4-carboxylic acid (3.0 g) in methanol (60 ml) was added dropwise to phosphorus oxychloride (2.55 g) under Ice cooling and stirring added. The mixture was stirred at the same temperature for 3.5 hours and then at room temperature for 30 minutes. After the reaction, the reaction mixture was poured into diethyl ether (400 ml). The precipitates were collected by filtration, washed with diethyl ether and then dried to give 2-methyl-7- [2- (2-aminothiazol-4-yl) glyoxylamido] -3-ce-phem-4-carboxylic acid hydrochloride, which Compound can also be referred to as i5 2-methyl-7- [2- (2-imino-2,3-dihydrothiazol-4-yl) glyoxylamido] -3-cephem-4-carboxylic acid hydrochloride, (2, 2 g), mp> 270 ° C, was obtained.

IR spectrum (Nujol):

201770.1700 (shoulder), 1665.1624.1515 cm "\

NMR spectrum (d6-dimethyl sulfoxide, ô):

1.44 (3H, d, J = 7Hz, 2-CH3)

3.6 to 4.1 (1H, m, 2-H)

25 5.15 (1H, d, J = 5Hz, 6-H)

5.82 (1H, dd, J = 5 and 8Hz, 7-H)

6.58 (1H, d, J = 6Hz, 3-H)

8.17 (1H, s, 5-H on the thiazole ring)

9.87 (1H, d, J = 8Hz, 7-CONH).

30th

Example 8

To a suspension of 2-methyl-7- [2-methoxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem-4-35 carboxylic acid (Synisomeres), also known as 2-methyl-7 - [2-meth-oxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) -acetami-do] -3-cephem-4-carboxylic acid (Synisomeres) (9.0 g ) In methanol (90 ml), concentrated hydrochloric acid (2.12 ml) was added with stirring at room temperature and the mixture was stirred at the same temperature for 7 hours. Diethyl ether was gradually added to the reaction mixture until crystals began to precipitate. The mixture was left to stand for 30 minutes. Then, the precipitated crystals were collected by filtration, washed with diethyl ether and then dried, whereby white crystals of 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-ce -phem-4-carboxylic acid hydrochloride (synisomer), which compound also as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3- cephem-4-carboxylic acid-hy-50 drochloride (Synisomeres) can be called (7.9 g) were obtained.

The remaining filtrate was concentrated until the total volume was reduced by half. Diethyl ether was gradually added to the concentrated filtrate until 55 crystals began to precipitate. The mixture was left to stand for 1 hour. The precipitated crystals were collected by filtration, washed with diethyl ether and then dried, whereby an additional amount of the same compound (0.5 g) was obtained.

60

IR spectrum (Nujol):

3300.3295.1780.1720.1660.1630.1300 cm "\

NMR spectrum (d6-dimethyl sulfoxide, ô):

ss 1.44 (3H, d, J = 7Hz 3.70 to 4.14 (1H, m)

3.94 (3H, s)

5.10 (1H, d, J = 5Hz)

5.84 (IH, d, J = 5Hz)

6.59 (IH, d, J = 6Hz)

6.94 (IH, s).

To a suspension of 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (Synisomeres), which compound also as 2-Me -thyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid hydrochloride (Synisomeres), (7, 7 g) in water (77 ml) was added a saturated aqueous sodium bicarbonate solution (44 ml). The solution thus obtained was adjusted to pH 3 by 1N hydrochloric acid and then left to stand in a cool place for 1 hour. The precipitated crystals were collected by filtration, washed with water and then dried, whereby a white powder of 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem- 4-carboxylic acid (synisomeres), also known as 2-methyl-7- [2-meth-oxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4- carboxylic acid (Synisomeres) can be called (6.67 g), mp 196 to 240 ° C (dec.), was obtained.

IR spectrum (Nujol):

3470.3310.3200.1790.1655.1620.1530.1295.1055 cm "\

NMR spectrum (d6-dimethyl sulfoxide, ô):

1.48 (3H, d, J = 8Hz)

3.65 to 4.08 (1H, m)

3.84 (3H, s)

5.10 (1H, d, J = 5Hz)

5.84 (lH, d, J = 5Hz)

6.54 (1H, d, J = 6Hz)

6.72 (1H, s).

The following compounds were obtained in a similar manner:

1) 2-Methyl-7- [hydroxy-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, which compound also as 2-methyl-7- [2 -hydroxy-2- (2-imino-2,3-dihydrothi-azol-4-yl) -acetamido] -3-cephem-4-carboxylic acid hydrochloride, mp> 250 ° C.

2) 2,2,2-Trichloroethyl-2-methyl ~ 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres), also known as 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (synisomeres) Mp 128 to 149 ° C (dec.).

3) 2,2,2-trichloroethyl-2-methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) -acetamido] -3-cephem-4-carboxylate (synisomer) which is also known as the 2nd , 2,2-trichloroethyl-2-methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres ), mp 175 to 178 ° C (dec.).

4) p-Nitrobenzyl-2-methyl-7- [2-hydroxyimino-2- (2-ami-nothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (syn-isome-res), which also as p-nitrobenzyl-2-methyl-7- [2-hydroxy-imino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-ce-phem-4-carboxylate (syn- Isomeric can be represented; pulverulent product.

5) 2-methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared.

6) 2-Methyl-7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn isomer), which is also known as 2-methyl 7- [2-ethoxyimino-2- (2-imino-

17 634 074

2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn-isomer) can be prepared.

IR spectrum (Nujol):

s 3350.1790.1730.1670.1630 cm ~ 1

NMR spectrum (D6-dimethyl sulfoxide, ô):

1.30 (3H, t, J = 6Hz)

1.47 (3H, d, J = 6Hz)

10 3.6-4.5 (1H, m)

4.25 (2H, q, J = 6Hz)

5.17 (1H, d, J = 5Hz)

5.92 (1H, d, d, J = 5 and 8Hz)

6.60 (1H, d, J = 6Hz)

15 6.97 (1H, s)

9.82 (lH, d, J = 8Hz)

7) 2-methyl-7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which

20 che can also be represented as 2-methyl-7- [2-isopropoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer) .

IR spectrum (Nujol):

25 3350.1780.1670.1600 cm ~ 1

NMR spectrum (D6-dimethyl sulfoxide, ô):

1.20 (6H, d, J = 6Hz)

1.43 (lH, d, J = 6Hz)

30 3.83 (1H, m)

4.27 (1H, m)

5.12 (1H, d, J = 5Hz)

5.87 (1H, d, d, J = 5 and 9Hz)

6.55 (lH, d, J = 6Hz)

3S 6.72 (1H, s)

7.23 (2H, broad s)

9.49 (1H, d, J = 9Hz)

8) 2-Methyl-7- [2-propoxyimino-2- (2-aminothiazol-4-yl) -40 acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7 - [2-propoxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared.

9) 2-Methyl-7- [2-butoxyimino-2- (2-aminothiazol-4-yl) -45 acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl -7- [2-butoxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isome-res) can be prepared.

10) 2-methyl-7- [2-isobutoxyimino-2- (2-aminothiazol-4-50 yl) -acetamido] -3-cephem-4-carboxylic acid (syn-isomer), which is also known as 2-methyl-7 - [2-isobutoxyimino-2- (2-imino-2,3-di-hydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared.

11) 2-Methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) -55 acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7 - [2-Hexyloxyimino-2- (2-imino-2,3-dihy-drothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomeres) can be prepared.

60 IR spectrum (Nujol)

3300.3200.1780.1670.1630 cm ~ 1

12) 2-Methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hexanoyloxymethyl ester

65 (syn isomer), which is also known as 2-methyl-7- [2-hexyloxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid- hexanoyloxymethyl ester (syn isomer) can be represented.

634 074

IR spectrum (Nujol)

3340.3200 (wide), 3150 (wide), 1790 (wide), 1750 to 1790, 1680.1630 cm "

Example 9

To a solution of 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres), the also as 2,2,2-trichloroethyl-2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylate ( Synisomeres) (0.1 g) in tetrahydrofuran (2 ml) and glacial acetic acid (0.25 ml), zinc powder (0.1 g) was added all at once with stirring, the temperature in an ice bath to below 25 ° C was held. The mixture was stirred at room temperature for 1 hour. Zinc powder (0.1 g) was further added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was filtered and the insoluble material was washed with a small amount of tetrahydrofuran. After the filtrate was combined with the washing water, the solvents were removed by spraying. To the residue was added a 5% aqueous sodium bicarbonate solution and ethyl acetate so that the aqueous layer had a pH of 7-8. The resulting mixture was filtered, and then the aqueous layer was separated. The aqueous layer was adjusted to a pH of 2 to 3 with 2N hydrochloric acid and then slightly concentrated. The aqueous layer thus obtained was subjected to column chromatography (Diaion HP 20 non-ionic adsorbent resin manufactured by Mitsubishi Chemical Industries). The column was washed with water and then successively eluted with 20% methanol and 40% methanol. The eluates containing the intended compound were collected and then lyophilized to give a white powder of 2-methyl-7- [2-methoxyimino-2- (2-aminothi-azol-4-yl) acetamido] -3- cephem-4-carboxylic acid (synisomeres), which is also known as 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihy-drothiazol-4-yl) acetamido] -3-cephem- 4-carboxylic acid (Synisomeres) can be called (0.015 g), mp 230 to 235 ° C (dec.), Was obtained.

Similarly, the following compounds were made:

1) 2-Methyl-7- [2-methoxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres), also known as 2-methyl-7- [2 -methoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) -acetamido] -3-cephem-4-carboxylic acid (Synisomeres), mp 174 to 204 ° C (dec.).

2) 2-methyl-7- [2-hydroxy-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, which compound also as 2-methyl-7- [2-hydroxy-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride, mp> 250 ° C.

3) 2-methyl-7- [2-hydroxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-hydroxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared.

IR spectrum (Nujol)

3250.1765.1625 cm-1

NMR spectrum (D6-dimethyl sulfoxide, ô)

ppm 1.42 (3H, d, J = 6.8Hz)

3.54-3.94 (1H, m)

5.23 (lH, d, J = 6Hz)

5.82 (1H, dd, J = 6 and 8Hz)

6.40 (IH, d, J = 6.8 Hz)

18th

6.64 (1H, s)

9.44 (1H, d, J = 8Hz)

4) 2-Methyl-7- [2-ethoxyimino-2- (2-formylaminothiazol-4-5 yl) acetamido] -3-cephem-4-carboxylic acid (syn-isomer), which is also known as 2-methyl-7 - [2-ethoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared.

io IR spectrum (Nujol)

3350, 3240, 3190, 1775, 1700, 1650, 1620 cm "1

5) 2-methyl-7- [2-isopropoxyimino-2- (2-formylaminothi-azol-4-yl) -acetamido] -3-cephem-4-carboxylic acid (syn-isome-

15 res), which is also known as 2-methyl-7- [2-isopropoxyimino-2- (2-formylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-car-bonic acid ( syn-isomer) can be represented.

IR spectrum (Nujol) 20 3480.3300.3180.1780.1740.1700.1660 cm "1

6) 2-methyl-7- [2-ethoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn isomer), which is also known as 2-methyl-7- [2-ethoxyimino-2- (2-imino-

25 2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hydrochloride (syn isomer) can be prepared.

IR spectrum (Nujol)

3350.1790.1730.1670.1630 cm "1

30th

7) 2-methyl-7- [2-isopropoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7- [2-isopropoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-

35 Isomeres) can be shown.

IR spectrum (Nujol)

3350.1780.1670.1600 cm "

40 8) 2-Methyl-7- [2-propoxyimino-2- (2-formylaminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7 - [2-propoxyimino-2- (2-formylimi-no-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared.

45

IR spectrum (Nujol)

3450.3300, 3050, 1780, 1730, 1690, 1660 cm "1

9) 2-Methyl-7- [2-propoxyimino-2- (2-aminothiazol-4-yl) -50 acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl-7 - [2-propoxyimino-2- (2-imino-2,3-dihydro-thiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can be prepared.

55 IR spectrum (Nujol)

3330, 3080, 1780, 1670 cm "1

10) 2-Methyl-7- [2-hexyloxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which

60 can also be represented as 2-methyl-7- [2-hexyloxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer) can.

IR spectrum (Nujol)

65 3300,3200,1780,1670,1630 cm "1

11) 2-methyl-7- [2-hexyloxyimino-2- (2-formylaminothi-azol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn-isome-

res), which also as 2-methyl-7- [2-hexyloxymino-2 ~ (2-for-mylimino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-car-bonic acid (syn -Isomeres) can be represented.

IR spectrum (Nujol)

3270, 3180, 1790, 1700, 1655 cm "1

Example 10

To a suspension of 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (syn isomer), which is also known as 2-methyl 7- [2-methoxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid (Synisomeres) (4.8 g) in water (48 ml) was dropwise added an IN aqueous sodium hydroxide solution at such a rate

that the pH of the mixture was not more than 7. The mixture was filtered and then lyophilized to give sodium 2-methyl-7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres), which is also referred to as sodium 2-methyl-7- [2-methoxyimino-2- (2-imino-2,3-dihy-drothiazol-4-yl) acetamido] -3-cephem-4-carboxylate (Synisomeres) can (4.8 g), mp> 250 ° C, was obtained. This compound was suspended in dry dimethylformamide (20 ml). Iodomethyl pivalate (2.30 g) was added to the suspension with vigorous stirring and cooling to 3 to 5 ° C. The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into a mixture of ethyl acetate (60 ml) and ice water (10 ml) and the mixture was shaken well. The ethyl acetate layer was separated and washed successively with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution. After drying the ethyl acetate layer over magnesium sulfate

19 634 074

the ethyl acetate was distilled off under reduced pressure. The remaining oil was pulverized in diethyl ether (25 ml), collected by filtration, and then dried to give pivaloyloxymethyl-2-methyl-7- [2-methoxyimino-2- (2-5 aminothiazol-4-yl) acetamido] -3 -cephem-4-carboxylate (Synisomeres), which also as PivaIoyloxymethyl-2-methyl-7- [2-meth-oxyimino-2- (2-imino-2,3-dihydrothiazol-4-yl) -acetamido] -3 -cephem-4-carboxylate (Synisomeres) can be called (1.44 g), mp 165 to 170 ° C (dec.), was obtained.

10th

IR spectrum (Nujol):

3340,1787,1757,1678,1637,1634,1283,1218,1158,1132, 1098,1034, 996 cm "K

15 NMR spectrum (d6-dimethyl sulfoxide, ô):

1.18 (9H, s),

1.47 (3H, d, J = 7Hz)

3.6 to 4.1 (3H, s)

5.18 (IH, d, J = 6Hz)

205.78 to 5.96 (3H, m)

6.70 (IH, d, J = 6Hz)

6.76 to 6.88 (IH, s)

9.65 (IH, broad d, J = 8Hz).

25 The 2-methyl-7- [2-hexyl-oxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid hexanoyloxymethyl ester (syn-isomer) was obtained by a similar procedure, which one also as 2-methyl-7- [2-hexyloxyimino-2- (2-imino-2,3-dihydrothiazo! -4-yl) acetamido] -3-cephem-4-carboxylic acid, he-30xanoyloxymethyl ester (syn-isomer) can be represented. IR spectrum (Nujol)

3340.3200 (wide), 3150 (wide), 1790 (wide),

1750 to 1790, 1680, 1630 cm "1

C.

Claims (3)

634 074 PATENT CLAIMS N ~ 7i. ^ 1. Process for the preparation of compounds of general H ~ N ff Ti A-CONH: \ Formula: 2 II N — n tJ-k- say R- N- ts. -CONH and their salts, characterized in that a compound of the general formula: N ir : 3-a- CONH where R1 is lower alkyl, R2 for a carboxy or an esterified carboxy group _ 3 3. stands, R3 represents an amino or an acylamino group and A is carbonyl, hydroxy (lower) alkylene, hydroxyimino (lower) alkylene or lower alkoxyimino (lower) a] kylene, the last two groups referring to group p -CONH- which have syn or anti configuration, and their salts, characterized in that a 20 in which R3a represents an acylamino group, or a salt thereof Compound of the general formula: subject to reduction to eliminate the acyl group. 4. The method according to claim 1 for the preparation of compounds of the general formula: (II) 25 CONH fVRl 30th or their reactive derivative on the amino group or their salt with a compound of the formula: N " R- t A-C00H (III) 35 and their salts, characterized in that a compound of the general formula: S , 3a or their reactive derivative on the carboxy group or their salt. 40 2. The method according to claim 1 for the preparation of compounds of the general formula: N ir vs CONH H wherein R3a represents an acylamino group, or a salt thereof j. y lì A-CONH —w ——— / ^ 'S R ^ "45 to eliminate the acyl group of treatment with a - Q y | | j | imino halogenating agent and an imino etherifying agent À— N> s and, if necessary, subsequent hydrolysis). 5. The method according to claim 1 for the preparation of Verbin-50 fertilizers of the general formula: N-1 and their salts, characterized in that one obtains a | 1—- A-CONH compound of the general formula: \ g / 55 and their salts, characterized in that a (Ib) 60 th compound of the general formula: R- wherein R3a represents an acylamino group, or a salt thereof 65 is subjected to hydrolysis to eliminate the acyl group. 3. Process according to spoke 1 for the preparation of compounds of the general formula: -TH- CONH 3rd 634 074 wherein R2a is an esterified carboxy group, or a salt thereof is subjected to hydrolysis to release the carboxy group. 6. The method according to claim 1 for the preparation of compounds of the general formula: 3 ^ | j — A-CONH R- and their salts, characterized in that a compound of the general formula: 3 ^ A-CONH R- esterified carboxy group, R3 stands for an amino or an acylamino group and A stands for hydroxyimino (lower) alkylene or lower alkoxyimino (lower) alkylene. 11. The method according to claim 10, characterized in that 5 that the synisomers are prepared. 12. The method according approached 11, characterized in that R1 stands for lower alkyl, R2 stands for a carboxy- or an esterified carboxy group, R3 stands for amino or acylamino and A stands for hydroxyimino (lower) alkylene or low- io alkoxyimino (lower) alkylene. 13. The method according to claim 12, characterized in that R1 is lower alkyl, preferably methyl, R2 is carboxy, carboxy-lower alkoxycarbonyl, which may have 1 to 3 halogen atoms, or lower alkanoyloxy (lower) alkoxy- i5 carbonyl, preferably carboxy, 2,2,2-trichloroethoxycarbonyl or pivaloyloxymethoxycarbonyl, R3 represents amino or lower alkanoylamino, which can have 1 to 3 halogen atoms, preferably amino, formylamino or trifluoroacetylamino, and A represents hydroxyimino (lower) alkylene or the lowest "alkoxyirnino (lower) alkylene, preferably hydroxyiminomethylene or methoxyiminomethylene. wherein R2a stands for an esterified carboxy group, or a salt 2S. The invention relates to a process for the preparation thereof for the release of the carboxy group is subjected to a reduction. 7. The method according to claim 1 for the preparation of compounds of the formula: R- 3 - * - CONH C00R- wherein R5 represents an ester portion of an esterified carboxy group of the formula: -COOR5 stands, and their salts, characterized in that one obtains a compound of the general formula: new 7-substituted 2-lower alkyl-2- or -3-cephem-4-carboxylic acid derivatives and their pharmaceutically acceptable salts which have antimicrobial activity.